Neurometabolic regulation of behavior and physiology in obesity, diabetes and neurological disease.

Our laboratory is interested in understanding the metabolic properties of neurons and glia at a mechanistic level in situ. Some of the most interesting, enigmatic and understudied cells in metabolic biochemistry are those of the nervous system. Defects in these pathways can lead to devastating neurological disease. Conversely, altering the metabolic properties of the nervous system can have surprisingly beneficial effects on the progression of some diseases. However, the mechanisms of these interactions are largely unknown.

We utilize biochemical and molecular genetic techniques to understand the molecular mechanisms that the nervous system uses to sense and respond to metabolic cues. We have uncovered novel neuronal nutrient sensing paradigms that act through unique metabolic enzymes to control body weight and diabetes susceptibility. We continue to explore novel neuron-specific enzyme function in metabolic processes as well as uncovering novel roles of canonical metabolic pathways in the nervous system. Furthermore, the unique makeup of the nervous system requires our laboratory to develop new technology and assays to facilitate our work.

Below are the broad areas that we are currently focusing on.

Deconstructing neurometabolic pathways. How does the nervous system utilize bioenergetic substrates and how does the disruption of these pathways affect animal behavior and physiology? Here we use tissue specific gain and loss of function mouse models to understand the biochemistry of the nervous system and how these metabolic pathways impact animal behavior and physiology. We are currently investigating several neuron-specific and canonical enzymes in fatty acid biochemistry.

Metabolic heterogeneity. The nervous system represents a unique challenge for biochemists in part because of the great diversity of neurons and glia, and the abundant metabolite shuttling that occurs between cells. To understand metabolism in the nervous system, we must understand how these different cells contribute uniquely to metabolic processes. Here we are developing novel tools to measure and manipulate metabolic pathways in single cells in vivo.

The evolution of metabolic adaptation. Nature has performed some of the most elegant experiments over an enormous time scale. Understanding how enzymes have changed over time or in species that are under different environmental stress can be invaluable to understanding ourselves. Here we try to ask many of the why questions in metabolism. Why has carbohydrate metabolism been selected for the brain over and over again in almost every species? What is the consequence of changing bioenergetics substrates?